DE1793259C3 - Process for the preparation of o- (2-hydroxyamino-acylamino) -phenylaryl ketones - Google Patents

Description

handlang of o-aminobenzophenone in chloroform with a lower alkyl or aryl sulfonyl halide, can also be prepared in chloroform added dropwise. When the addition is complete, the Reaction mixture heated on a steam bath for approximately 15 minutes to ensure optimal yields. Removal of the solvent and recrystallization gives the desired product.

The o- (2-hydroxyamino-acylamino) phenylaryl ketones prepared by the process according to the invention have anticonvulsant and sedative effects.

The following examples illustrate the invention.

example 1

15th

A mixture of 5-chloro-2- (2'-iodacetarpido) -benzophcnon (5.0 g), Hydroxy'amir.-hydrochloride (7.0 g), water (20 ml), sodium hydroxide solution (4 N, 20 ml ) and dimethylformamide (60 ml) is ^{stirred at room temperature for 1} l for ₂ hours, during which time a clear solution results. Water (100 ml) is added and the resulting solid collected and recrystallized from benzene to give 5-chloro-2 - (2 '- hydroxyamino - acetamido) - benzophenone, melting point 129-131 ° C. Yield 60%.

Analysis for C ₁₅ H ₁₃ ClN ₂ O ₃ :

Calculated ... C 59.10, H 4.30, Cl U, 64, N 9.21%; found .... C 59.38, H 4.16, Cl 11.70, N 9.00%.

Example 2

A mixture of 5-chloro-2- (2'-chloroacetamido) benzophenone (4.0 g), hydroxylamine hydrochloride (7.0 g), water (10 ml), sodium hydroxide (4N, 20 ml), dimethylformamide ( 100 ml) and sodium iodide (0.2 g) is stirred at 50 ⁰ C ^l / ₂ hour to obtain a clear solution. Water (100 ml) is added with cooling, and the precipitate formed is recrystallized from alcohol and then from benzene to yield 5-chloro-2- (2'-hydroxyamino-acetamido) benzophenone, melting point 129 to 131 ⁰ C. Yield 30 %.

Production of the sulfonoxy starting products

45

a) To a solution of 2-amino-5-chlorobenzophenone (40 g) in chloroform (150 ml) is added dropwise a solution of acetylglycollyl chloride (26 g) in chloroform (60 ml) was added. The solution will be warm during the addition, and when the addition is complete the reaction mixture is turned on the steam bath Heated for 15 minutes. The solvent is removed under reduced pressure and the residue is recrystallized from ethanol and gives 2- (2'-acetoxyacetamido) -5-chlorobenzophenone, melting point 121 up to 123 ° C. Yield 87%.

Analysis for C ₁₇ H ₁₄ ClNO ₄ :

Calculated ... C 61.5, H 4.25, N 4.22, Cl 10.7%;
found .... C 61.48, H 4.30, N 4.07, Cl 10.9%.

b) A solution of 2- (2'-iodo-acetamido) -5-chlorobenzophenone (100 g), sodium acetate (75 g) and glacial acetic acid (600 ml) is refluxed for 2 hours. The reaction mixture is diluted and the product, crystallized from ethanol, gives 2 - (2 '- acetoxy - acetamido) - 5 - chlorobenzophenone. Melting point 121 to 123 ° C. Yield 66%.

c) To a suspension of 2- (2'-acetoxy-acetamido) -5 - chlorobenzophenone (66.6 g) in ethanol (550 ml), a solution of sodium hydroxide (8 g) in water (60 ml) is added with stirring. The Stirring is continued until the solution is clear. water (750 ml) is added and the product is thereby precipitated, the 2- (2'-hydroxyacetamido) -5-chlorobenzophenone recrystallized from ethanol (55 g), melting point 150 to 152 "C. Yield 94%.

Analysis for C ₁₅ H _n ClNO ₃ :

Calculated ... C62.18, H4.18, N4.84, Cl 12.24%; found .... C 62.29. H 4.15, N 4.72, Cl 12.30%.

d) p-Bromophenylsulfonyl chloride (28 g) is added to a solution of 2- (2'-hydroxy-acetamido) -5-chlorobenzophenone (15 g) in triethylamine (200 ml). The reaction mixture is heated on the steam bath for about 30 minutes, cooled and diluted with ice water to give a precipitate which, collected and recrystallized from acetonitrile, is 2- (2'-p-bromophenyl-sulfonoxy-acetamido) -5-chlorobenzophenone (17 g), melting point 150 to 152 ^: C, results.

Analysis for C ₂₁ H ₁₅ BrClNO ₅ S:

Calculated ... C 49.58, H 2.97, N 2.75, Br 15.71,

Cl 6.97, S 6.30%; Found ... C 49.98, H 2.84, N 2.93, Br 15.6

Cl 6.80, S 6.30%.

e) To a solution of 2- (2'-Hydroxy-acetamido) -5-chloro-benzophenone (15 g) in triethylamine (200 ml) is added p-toluenesulfonyl chloride 1.21 g). The Product is separated off as described above and recrystallized from acetonitrile to give 2- (2'-p-toluenesulfonoxy-acetamidoJ-S-chlorobenzophenone (13 g. 76%). Melting point 148 to 150 "C.

Analysis for C ₂₂ H ₁₈ ClNO ₅ S:

Calculated ... C 59.52, H 4.09. Cl 7.99, S 7.22%; found .... C 59.57, H 3.97, Cl 8.0. S 7.2%.

2- (2'-Methylsulfonoxyacetamido) -5-chlorobenzophenone, melting point 120 to 122 ^° C., is prepared in a similar manner from 2- (2'-hydroxy-acetamido) -5-chlorobenzophenone and methylsulfonyl chloride.

Analysis for C ₁₆ H ₁₄ ClNO ₅ S:

Calculated ... C 52 24. H 3.84, N 3.81. Cl 9.64.

S 8.70%;
found .... C, 52.30. H 3.78. N 3.83, Cl 9.7,

S 9.0%.

Yield 10% using 7.2 g of 5-chloro-2- (2'-hydroxy-acetamido) -benzophenone.

g) Following the procedure in paragraph a) above, a solution of 2-p-toluenesulfonoxyacetyl chloride is obtained (Bull. Soc. Chim. France 1948, 995) in chloroform with 2-amino -5-chlorobenzophenone in Treated chloroform to give 2- (2'-p-toluenesulfonoxyacetamido) -5-chlorobenzophenone. Melting point 148 to 150 ° C after recrystallization from acetonitrile receive.

h) Following the procedure of paragraph a) above, a solution of 2-amino-5-chlorobenzophynone is obtained (14 g) in chloroform (50 ml) 2-phenyl-

sulfonoxy-acetyl chloride (Bull. Soe. Chim. France. 1948, 995) was added in chloroform. The mixture is heated on the steam bath for 20 minutes and the solvent removed in vacuo. The residue solidifies and yields auskristaliisiert from ethanol 5 (about 800 ml), 2- (2'-phenyl-sulfonoxy-acetamido> 5-chlorobenzophenone (21 g, 81So), mp 130 to 132 ⁰ C.

Analysis for C ₂₁ H ₁₆ ClNO ₅ S:

Calculated ... C 58.67. H 3.75. Cl 8.25, N 3.26.

S 7.46%;
found .... C 58.56. H 3.62. Cl 8.56, N 3.56

S 7.5%.

Example 3 ' ⁵

To 2- (2'-p-bromophenylsulfonoxy-acetamido) -5-chlorobenzophenone (51g) in methyl cellosolve (150 ml), heated to 85 ° C, a solution of hydroxylamine hydrochloride (10 g), sodium hydroxide (5 g) and water (20 ml) added. The temperature is held at 80 to 90 ^° C. for 15 minutes and the mixture is then cooled and diluted with water. The product, collected and recrystallized from benzene, gives 2- (2'-hydroxyamino-acetamido) -5-chlorobenzophenone, melting point 129 to 131 ^° C.

Example 4

To a solution of 2- (2'-p-toluenesulfonoxy-acetamido) -5-chlorobenzophenone (4.4 g) in methyl cellosolve (150 ml) at 85 ° C is a solution of hydroxylamine hydrochloride (10 g) and sodium hydroxide (5 g) in water (20 ml) were added. After 15 minutes at 85 ° C the mixture is cooled and diluted with water and the collected product becomes benzene crystallizes out and gives 2- (2'-hydroxyaminoacetamido) -5-chlorobenzophenone (1.6 g), melting point 129 to 13Γ C.

Using the same procedure, 2- (2'-hydroxyamino - acetamido) - 5 - chlorobenzophenone from 2- (2'-phenylsulfonoxy - acetamido) - 5 - chlorobenzophenone and hydroxylamine.

Example 5

To a solution of 3.7 g of 5-chloro-2- (2'-methylsulfonoxy-acetamidoj-benzophenone a solution of 10 g in 150 ml of methylcellosolve at 85 ° C Hydroxylamine and 5 g of sodium hydroxide in 20 ml of water were added. After standing at 85 ° C for 15 minutes the mixture is cooled and diluted with water and the crystallized product is collected from benzene, whereby the 5-chloro-2- (2'-hydroxyamino-acetamido) -benzopheiion from melting point 129 to 131 ° C. receives.

Example 6

Ethanol (3960 cm ³ ) is added to a solution of 75% hydroxylamine sulfate (1400 g, 6.4 mol) in water (2100 cm ³ ) and the entire solution is heated to 60 to 62 ° C. 50% sodium hydroxide solution (844 g, 10.6 mol) is added to this rapidly stirred solution. To the resulting mixture is immediately added 4'-chloro-2 '- (o-chlorobenzoyl) -2-iodacetaniüd (694 g, 1.6 mol) and stirring is continued at 70 to 75 ^° C. for 30 minutes.

The product begins to crystallize during this period. Cold water (8600 cm ³ ) is then added over 15 to 20 minutes and the thick mixture is stirred at 30 to 35 ° C. for 1 hour. The white solid is separated by filtration, ^{resuspended and stirred in water (6400 cm 3} ) at 30 to 35 "C for 5 minutes, filtered, ^{washed on the funnel with water (400 cm 3} twice) and placed in an air-heated oven at 45 to 50 ° C. In this way, 4'-ChlGr-2 '- {o-chlorobenzoyl) -2-hydroxyaminoacetanilide (516 g, 95%) with a melting point of 153 to 155 ° C. is obtained.

Example 7

7.0 g of 75% strength hydroxylamino sulfate are added to a solution of 20 ml of ethanol and 11 ml of water. There are sodium hydroxide (50% solution, 4.22 g) and 3.45 g of 5-bromo-2- (2'-bromoacetamido) -4 "-chlorbenzophenon added and the temperature during J hour at 70 to 75 ⁰ C. The mixture is then added to 45 ml of water to precipitate the 5-bromo-2- (2'-hydroxyaminoacetamido) -4 "-chlorobenzophenone.

For identification, the product obtained is redissolved in 10 ml of ethanol and acidified with 3N hydrochloric acid. Cooling and dilution of the solution with water leads to the deposition of a product in the form of crystals with a melting point of 249 to 250 ^° C. (decomposition). Recrystallization from ethanol gives 7-bromo-5- (p-chlorophenyl) -l, 3-dihydro-2 Hl, 4-benzodiazepin-2-one-4-oxide in the form of a pure product with a melting point of 260 to 261 ° C (Decomposition).

Analysis for C ₁₅ H ₁₀ N ₂ ClBrO ₂ :

Calculated ... C 49.27, H 2.76. N 7.66, Cl 9.69.

Br 21.86%;
found .... C 49.29, H 2.63. N 7.65, Cl 9.74,

Br 21.94%.

Example 8

To a suspension of 14.8 g of hydroxylamine sulfate in 350 ml of methanol, 10.2 g of sodium methylate, dissolved in 350 ml of methanol, added. After adding 29.4 g of 5-chloro-2- (2'-bromopropionamido) benzophenone the mixture is refluxed under a nitrogen atmosphere for 16 hours. It becomes a slurry of 7.4 g of hydroxylamine sulfate and 5.1 g of sodium methylene in 500 ml of methanol are added and the mixture is again heated under reflux for 24 hours. The insoluble salts are filtered off, and the filtrate is used with water to separate 5-chloro-2- (2'-hydroxyaminopropionamido) -benzophenone diluted as a solid.

Part of the material thus obtained is dissolved in acetic anhydride with heating for identification. On cooling the solution, 7-chloro-3-dihydro-3-methyl-5-phenyl-2 separates H-1,4-benzodiazepin-2-one-4-oxide (melting point 268 ° C., decomposition).

Analysis for C _lf , H _u ClN ₂ O ₂ :

Calculated ... C 63.92, H 4.36, N 9.32, Cl 11.79%: found .... C 64.20. H 4.48, N 9.07. Cl 11.59%.

Claims (1)

Claim: Process for the preparation of o- (2-hydroxyamino-acylamino) -phenylaryl ketones the general formula R ¹ N-CO-C-NHOH R ² COAr wherein the ring A can be unsubstituted or substituted by one or more lower alkyl groups, chlorine, bromine, nitro, halogen-lower-alkyl or alkylsulfonyl groups, R is hydrogen, lower-alkyl or lower-aralkyl groups, R ¹ and R Hydrogen or one or two lower-alkyl, aralkyl or aryl groups and Ar is an aryl or heteroaromatic radical, where, when R, R ¹ and R ^{2 are} hydrogen and Ar is a phenyl radical, ring A in the 5-position is not can be substituted by chlorine, characterized in that a ketone of the general formula R ¹ N- / -CO- -c - A. I. CO R ² -Ar 30th 35 where Z is bromine, iodine, chlorine or an organic sulfonoxy radical, with: reacts hydroxylamine, where, when Z is chlorine, a small amount of a water-soluble iodized salt is present have to be. 45 The subject matter of the invention can be found in the claim. In the general formula of the claim, Ar can in particular 1- or 2-naphthyl, but preferably tinen monocyclic aryl radical such as phenyl or a phenyl radical, which by one or more, in the reaction non-interfering groups such as halogen, e.g. B. chlorine or bromine, a lower-alkyl. lower alkoxy, Halo-lower-alkyl, such as. B. the trifluoromethyl, © the one alkyl, such as. B. the methylsulfonyl group may be substituted or a 2- or 3-furyl, 2- or 3-thienyl or 2-, 3- or 4- pyridyl radical. The term lower-alkyl as used herein includes the methyl, ethyl, propyl, isopropyl, η-butyl and the isoamy group; lower alkenyl and Alkynyl groups such as allyl, methallyl, ethynyl, propenyl and vinyl groups; and lower cycloalkyl groups such as the cyclopropyl, cyclobutyl and cyclopentyl groups. Lower-alkyl groups include those Understand groups with up to 6 carbon atoms. A lower aralkyl group is an aralkyl radical to understand with up to 9 carbon atoms, ζ. Β benzyl or phenethyl. Under a lower alkoxy group is to be understood as a group with up to 6 carbon atoms. The radicals R ₁ and R ₂ can, for. B. a methyl, ethyl, propyl, isopropyl, η-butyl, t-butyl or isoamyl group or with the formation of a hydrocarbon ring such as a lower cycloalkyl group, e.g. B. the cyclopropyl, cyclobutyl and cyciopentyl group. They can also represent unsaturated groups such as the vinyl, ethynyl and propenyl groups. If they are Arylreue, they can in particular denote the phenyl radical or a phenyl radical which is substituted by groups which do not interfere in the reaction, such as halogen, a lower-alkyl group and a hydroxyl group. If they represent aralkyl radicals, they can in particular denote the benzyl or phenylethyl radical, in which the phenyl group can be unsubstituted or substituted in a manner similar to that described above. The 2-substituent in the ketone used as starting material of the general formula des Claim can, if it represents an organic sulfonoxy radical, z. B. a lower-alkyl or an arylsulfonoxy substituent such as a methylsulfonoxy group or a phenylsulfonoxy group such as B. a phenylsulfonoxy, p-halophenylsulfonoxy- or p-toluenesulfonoxy group. The reaction with hydroxylamine according to the invention also includes the reaction with a soluble salt same one. Contrary to what would normally be expected, even in the presence of a large excess of hydroxylamine, the process of the invention results in an essentially selective displacement of the 2-substituent rather than the expected formation of an oxime to form an ο- (2- Hydroxyamino - acylamino) - phenylaryl ketone in good yield. The reaction is preferably carried out at a pH of substantially 4 to substantially 9 and preferably in a mixed solvent containing water and a water-soluble organic solvent such as methanol, ethanol, dioxane or dimethylformamide in order to obtain an optimal yield. The reaction can also be carried out in non-aqueous media, either with or without a water-soluble organic solvent. Preferably, the reaction at temperatures in the range of about 30 ⁰ C to the reflux temperature of the solvent mixture is carried out for a period of about _V4 hour to about 2 hours. The reaction mixture can then be diluted with water in order to precipitate the ο - (2 - hydroxy - amino - acylamino) - phenylaryl ketone in an easily isolatable form. The o- (2-substituted - Acylamino) - phenylaryl ketones can by reacting an o-aminophenylaryl ketone with a suitable 2-substituted acyl halide or anhydride or carbodiimide, e.g. B. with a 2-haloacyl halide, anhydride or carbodiimide or a 2-organic sulfonoxyacyl halide or anhydride or carbodiimide, e.g. B. a 2-lower-alkyl or a 2-aryl-sulfonoxyacyl halide, anhydride or carbodiimide. For example, an o- (2-nicdrigalkyl- or arylsulfonoxy-acetamido) -benzophconone can be